Chronic disease represents a considerable burden on society. Worsening this is the increased risk of chronic disease patients to develop a diagnosis of depression. Pro-inflammatory cytokines that occur as a result of chronic disease are hypothesized to represent a major portion of the pathological mechanism of such comorbid depression, Even so, not every patient with a chronic disease develops this specific comorbidity, and it is unknown what factors contribute to the variability of depression expression in this patient population. One potential biomarker for depression predictability is the expression of brain-derived neurotrophic factor (BDNF). Not only has BDNF been studied for its relation to depression status in human and in rodents, it has been shown to interact with pro-inflammatory cytokines and suppress inflammation. Furthermore, neuroimmune activation, which is thought to be the mechanism by which pro-inflammatory cytokines induce behavioral changes, also interferes with BDNF signaling. Specifically, this proposal will test the hypothesis that BDNF expression is a determinative factor in the magnitude of neuroimmune activation and subsequent depressive-like behaviors following peripheral inflammation. To address this hypothesis, Aim 1 will establish that BDNF deficient mice experience more exaggerated depressive-like behaviors following peripheral inflammation concordant with more pronounced neuroimmune activation. This will be accomplished in an established mouse model of inflammation-induced depressive-like symptoms followed by characterization of region specific changes in the central neuroimmune response. Specific Aim 2 will determine if increasing central BDNF expression during peripheral inflammation protects against neuroimmune activation and the development of depressive-like behavior. The final specific aim of this proposal will utilize ex vivo and in vitro approaches to directly elucidate the consequences of altering BDNF expression on microglial TrkB receptor signaling, microglial activation and neurotoxic metabolism of tryptophan along the kynurenine pathway. Defining the impact of BDNF expression on microglia activation and the involvement of the metabolism tryptophan and kynurenine will not only extend our understanding of the pathogenesis of comorbid depression during inflammation, but also it may identify novel diagnostic or therapeutic targets. Further, successful completion of the proposed aims will provide the first data investigating the in vivo interactions of inflammation, BDNF expression, and depressive-like behaviors. Together with a variety of academic, training and enrichment activities that are woven into the overall training plan; this proposal outlines a thorough multidisciplinary and well-balanced framework to advance a trainee towards the career goal of becoming an independent investigator.